IGF-I stimulates growth of both normal and neoplastic mammary gland, and genetic studies have shown that IGF-I and IGF-IR signaling are needed for complete mammary development. IGFs are potent mitogens for breast cancer cells, and IGF-IR and its downstream signaling intermediate IRS-1 are hyperactive in breast tumors compared to normal breast. Elevated IGF signaling intermediates are associated with a poor prognosis in breast cancer. Strategies to block IGF action have been successful in inhibiting breast cancer growth, providing proof of principle for the pharmaceutical development of IGF-IR inhibitors. Furthermore, the IGF system has a strong positive interaction with the ER pathway, which is already known to be elevated in premalignant vs. normal breast tissue. We have shown that this interaction is bidirectional ERalpha can increase expression of multiple IGF signaling intermediates and sensitize cells to IGFs, while IGF-I can specifically activate ERalpha even in the absence of estrogen. Despite the wealth of literature implicating IGFs in breast cancer proliferation and demonstrating their interaction with the ER system, almost nothing is known about the importance of IGFs during onset and progression of premalignant breast disease, even though elevated ERalpha ?is clearly involved in this process. We hypothesize that IGFs are important drivers of premalignant progression in mammary tissue, due in part to upregulation of IGF signaling and IGF-mediated growth by estrogen. We will test this hypothesis by examining whether IGF and its signaling pathways regulate premalignant progression, and whether agents that block IGF-IR action can prevent this progression. Additionally, we will investigate how ER? interacts with IGF pathway in this progression. The specific questions to be addressed are: 1) Does increased IGF-I signaling promote premalignant progression in the mammary gland? 2) Can blockade of the IGF pathway prevent or delay premalignant disease and its progression to mammary cancer in mouse models? 3) Does cross-talk between ER and IGF-I regulate the growth and progression of premalignant disease and breast cancer? In this proposal we will take a multidisciplinary approach, making use of the expertise and materials available from the PPG participants and cores, and using xenografts, cell lines, mouse models, and human breast specimens, to address the role of IGFs in premalignant breast disease progression.